Study of Matched Unrelated Donor T Cell Infusion for Hematologic Malignancies After Allo-HSCT

Phase 1

Withdrawn

• Conditions: Leukemia; Myelodysplastic Syndromes; Lymphomas; Multiple Myeloma; Other High-risk Hematological Malignancies
• Interventions: Biological: rivogenlecleucel; Drug: Rimiducid

• Registration Number: NCT02786485
• Lead Sponsor: Bellicum Pharmaceuticals

Brief Summary

This is a Phase I, multicenter, open-label, non-randomized study of matched unrelated donor BPX-501 T cell infusion in adult subjects with hematological malignancies presenting with recurrent disease minimal residual disease (MRD) post-allogeneic transplant.

Detailed Description

Un-manipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. The addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral antigens, as well as against cancer antigens, might provide a clinical benefit. However, an expected side effect of the presence of mature T cells is the potential occurrence of acute graft-versus-host disease (aGvHD). The use of a suicide gene switch which would trigger the initiation of the apoptosis of the alloreactive T cells by the infusion of a drug would represent the potential optimal strategy for restoring early immunity with a built in "safety switch" against GvHD side effects. Evidence has emerged that low-dose DLI followed by dose escalation can achieve higher clinical response rate with lower GvHD occurrence. Optimization of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the consistent ability to separate GvHD from graft-versus-tumor (GvT) activity and improve the safety of DLI treatment. Our strategy is to infuse escalating doses of manipulated T cells (from the same donor who provided the original hematopoietic stem cell graft) in adults and children with recurrent or minimal residual disease (MRD) hematologic malignancies post-allogeneic transplant to accelerate immune reconstitution thus improving graft versus leukemic effect while reducing the severity of GvHD.

Study Timeline

• Study Start: 2016-05
• Study First Submitted: 2016-05-26
• Study First Submitted QC: 2016-05-31
• Study First Posted: 2016-06-01
• Primary Completion: 2018-12
• Study Completion: 2018-12
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-01
• Last Update Posted: 2020-10-05

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Subjects aged ≥ 18 yrs and ≤ 65 yrs;

• Clinical diagnosis of one of the following hematological malignancies:

  • Leukemia
  • Myelodysplastic Syndromes
  • Lymphomas
  • Multiple Myeloma
  • Other high-risk hematological malignancy eligible for stem cell transplantation per institutional standard;

• Recurrent disease that presents ≥100 days after, or minimal residual disease (MRD) that presents ≥ 30 days following a hematopoietic stem cell transplant (HSCT) using a matched unrelated donor located through the National Marrow Donor Program (NMDP);

• Life expectancy >10 weeks;

• Signed donor and patient/guardian informed consent;

• A 8/8 genotypic identical match as determined by high resolution typing for the following genetic loci: human leukocyte antigen (HLA)-A, HLA-B, HLA-C and HLA-DRB1;

• Performance status: Karnofsky score > 50%;

• Subjects with adequate organ function as measured by:

  • Bone marrow:

    • > 25% donor T-cell chimerism post-transplant
    • Absolute neutrophil count (ANC) >1 x 109/L

  • Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 45%

  • Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC), diffusion capacity of lunch for carbon monoxide (DLCO) ≥ 50% predicted (corrected for hemoglobin)

  • Hepatic: direct bilirubin ≤ 3x upper limit of normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5x ULN

  • Renal: creatinine ≤ 2x of ULN for age.

Exclusion Criteria

• ≥ Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of screening;
• Active central nervous system (CNS) involvement with malignant cells (≤ 2 months prior to consenting);
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings); the principal investigator is the final arbiter of this criterion;
• Positive HIV serology or viral RNA;
• Pregnancy (positive serum β human chorionic gonadotropin [HCG] test) or breast-feeding;
• Fertile men or women unwilling to use effective forms of birth control or abstinence for one year after transplantation;
• Bovine product allergy.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Rivogenlecleucel & Rimiducid	rivogenlecleucel	All subjects will receive 3 courses of rivogenlecleucel (BPX-501 T cells) infusions at 30 day intervals with 2 escalating dose levels (DL). DL1 on Day 0 and DL2 on Days 30 and 60. Escalating doses of rimiducid (AP1903) (0.1 mg/kg and 0.4 mg/kg) will be investigated for the treatment of aGvHD after rivogenlecleucel infusion.
Rivogenlecleucel & Rimiducid	Rimiducid	All subjects will receive 3 courses of rivogenlecleucel (BPX-501 T cells) infusions at 30 day intervals with 2 escalating dose levels (DL). DL1 on Day 0 and DL2 on Days 30 and 60. Escalating doses of rimiducid (AP1903) (0.1 mg/kg and 0.4 mg/kg) will be investigated for the treatment of aGvHD after rivogenlecleucel infusion.

Primary Outcome Measures

Name	Time	Method
Adverse events	30 days after last dose of study drug (BPX-501 and/or rimiducid)	Number of adverse events after study drug (BPX-501 and/or rimiducid) administration as a measure of safety